Intranasal Delivery of Mesenchymal Stem Cell Derived Exosomes Loaded with Phosphatase and Tensin Homolog siRNA Repairs Complete Spinal Cord Injury

Guo, Shengming; Perets, Nisim; Betzer, Oshra; Ben-Shaul, Shahar; Sheinin, Anton; Michaelevski, Izhak; Popovtzer, Rachela; Offen, Daniel; Levenberg, Shulamit

doi:10.1021/acsnano.9b01892

Cited by 279 publications

(245 citation statements)

References 97 publications

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“…A multimodal approach provides the potential to make use of the advantages of each modality while reducing the overall drawbacks. Exosomes measureable by both CT and FLI can be tracked in vivo using CT, and then more precisely ex vivo with FLI (Guo et al, 2019). Also, this approach allows for self-validation, since a measured result can be confirmed by the other modalities (C. P. Lai, Mardini, Ericsson, et al, 2014;Yuki Takahashi & Takakura, 2015).…”

Section: Discussionmentioning

confidence: 99%

Advances in imaging strategies for in vivo tracking of exosomes

Betzer

Barnoy

Sadan

et al. 2019

WIREs Nanomed Nanobiotechnol

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Exosomes have many biological functions as short‐ and long distance nanocarriers for cell‐to‐cell communication. They allow the exchange of complex information between cells, and thereby modulate various processes such as homeostasis, immune response and angiogenesis, in both physiological and pathological conditions. In addition, due to their unique abilities of migration, targeting, and selective internalization into specific cells, they are promising delivery vectors. As such, they provide a potentially new field in diagnostics and treatment, and may serve as an alternative to cell‐based therapeutic approaches. However, a major drawback for translating exosome treatment to the clinic is that current understanding of these endogenous vesicles is insufficient, especially in regards to their in vivo behavior. Tracking exosomes in vivo can provide important knowledge regarding their biodistribution, migration abilities, toxicity, biological role, communication capabilities, and mechanism of action. Therefore, the development of efficient, sensitive and biocompatible exosome labeling and imaging techniques is highly desired. Recent studies have developed different methods for exosome labeling and imaging, which have allowed for in vivo investigation of their bio‐distribution, physiological functions, migration, and targeting mechanisms. These improved imaging capabilities are expected to greatly advance exosome‐based nanomedicine applications. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

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Section: Discussionmentioning

confidence: 99%

Advances in imaging strategies for in vivo tracking of exosomes

Betzer

Barnoy

Sadan

et al. 2019

WIREs Nanomed Nanobiotechnol

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“…Guo et al tested in experimental SCI models loaded with PTEN-siRNA-MSC-exo. The exosome could able to carry PTEN-siRNA to the target tissues e ciently and augment the regenerative effect by promoting more robust axon regeneration after SCI [35].…”

Section: Discussionmentioning

confidence: 99%

Local delivery of USC-derived Exosome Carrying ANGPTL3 Enhance Spinal Cord Functional Recovery After Injury by Promoting Angiogenesis

Yan

Cao

Chen

et al. 2020

Preprint

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Abstract Background: Spinal cord injury (SCI) is a devastating clinical diseasewithout effectivetherapeuticapproach recently. In this study, we aim to investigate the effect of locally injection with exosome derived human urine stem cell (USC) embedding with hydrogelcould improve the spinal cord functional recovery after injury and the underlying mechanism.Methods:Exosome were isolate from USC andidentified by transmission electron microscopy and western blot. Functional assays using human umbilical vein endothelial cell (HUVEC) in vitro were performed to assess the effects of USC-Exosdeliverythe angiopoietin-like protein 3 (ANGPTL3) on tube formation and migration as well as their regulatory role in the PI3K/AKT signaling pathway activation. In vivo experiment we locally injection with exosome derived USC embedding with hydrogel for treatment of SCI. The effects of USC-Exos on functional recovery in spinal cord injury mice were tested by measuring motor evoked potential, histological and neovascular numbers. Meanwhile, the role of the candidate protein ANGPTL3 in USC-Exo for promoting angiogenesisin SCI was assessed.Results:In current study, we demonstrate that when given locallyinjection with exosomederivedhuman urine stem cell (USC) embeddingwith hydrogelcould pass the spinal cord blood brain barrier and delivery the angiopoietin-like protein 3 (ANGPTL3) to the injured spinal cord region. In addition, the administration of exosome derived from human USC could enhance spinal cord neurological functional recovery by promoting angiogenesis.The mechanism studies revealed that ANGPTL3 are enriched in USCexosome(USC-Exo) and required for USC exosome promoting angiogenesis. Functional studies further confirmed the effects caused by exosome derived from USC on angiogenesis wasmediated by PI3K/AKT signaling pathway. Conclusion:Collectively, our results indicated that USC derived exosome serve as a critical regulator of angiogenesis by transferring ANGPTL3 and may represent a promising novel therapeutic agent for SCI repair.

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“…Exosomes were suspended in 70ml PBS and were centrifuged for 90 minutes at 100,000g at 4˚C. The pellet was suspended in 200 µL of PBS [14][15][16] .…”

Section: Exosomes Labelingmentioning

confidence: 99%

“…We have previously shown that MSC-exo migrate to damaged tissues in the brain after intranasal administration [14][15][16] . In the BTBR mice model of autism we saw MSC-exo accumulating in the areas of the frontal cortex and the cerebellum while in WT C57BL/6Jmice we could not detect any accumulation and the MSC-exo evacuated out of the brain within 24h.…”

Section: Msc-exo Cross the Blood Brain Barrier After Intranasal Adminmentioning

confidence: 99%

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Exosomes derived from mesenchymal stem cells improved core symptoms of genetically modified mice model of autism Shank3B

Perets

Oron

Herman

et al. 2020

Preprint

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Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with main core symptoms including deficits in social-communication abilities and repetitive behaviors/restricted interests. ASD affects 1 of 88 children worldwide and currently there is no sufficiently effective treatment that alleviates its core deficits. In our previous studies, we have shown that both MSC and MSC-exo can ameliorate core ASD-like symptoms of the BTBR multifactorial mouse model of autism. Furthermore, we have demonstrated that the MSC-exo migrate to distinct neuropathological areas in several mouse models, including the frontal cortex and cerebellum in BTBR mice. In contrast to BTBR mice, which is a multifactorial model of autism, the Shank3B KO mouse is used to study ASD which develops due to a specific genetic mutation. Here we demonstrate that intranasal treatment with MSC-exo improves the social behavior deficit in multiple paradigms, increases vocalization and reduces repetitive behaviors. We also observed an increase of GABRB1 in the prefrontal cortex. Taken together, our data indicate that intranasal treatment with MSC-exo improves the core ASD-like deficits of in this mouse model autism and therefore has the potential to treat ASD patients carrying the Shank3 mutation.

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Intranasal Delivery of Mesenchymal Stem Cell Derived Exosomes Loaded with Phosphatase and Tensin Homolog siRNA Repairs Complete Spinal Cord Injury

Cited by 279 publications

References 97 publications

Advances in imaging strategies for in vivo tracking of exosomes

Advances in imaging strategies for in vivo tracking of exosomes

Local delivery of USC-derived Exosome Carrying ANGPTL3 Enhance Spinal Cord Functional Recovery After Injury by Promoting Angiogenesis

Exosomes derived from mesenchymal stem cells improved core symptoms of genetically modified mice model of autism Shank3B

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